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Background Data on the outcome of occupational asthma (OA) are heterogeneous. Objective To assess the impact of being part of a specific cluster at diagnosis on the long-term outcome of diisocyanate-induced OA. Methods We collected data from 56 patients who had a diagnosis of OA confirmed by a positive specific inhalation challenge. Patients sensitized to toluene diisocyanate were allocated to cluster 1 or 2 based on a tree analysis, using the 3 variables relevant for cluster segregation identified in a previous study: age, body mass index, and forced expiratory volume in 1 second/forced vital capacity at diagnosis. Patients sensitized to methylene diisocyanate were allocated to cluster 3, as in previous study. We defined OA remission when a patient had met a total of 3 criteria: no asthma symptoms and no antiasthma therapy for the last year, as well as having normal lung function. Results At follow-up, 16 patients showed OA remission. They exhibited better lung function, less bronchial hyperreactivity, as well as younger age at diagnosis. Twenty-eight patients were allocated to cluster 1, 10 to cluster 2, and 18 to cluster 3. The percentage of patients with OA remission was higher in cluster 2 (50% vs 25% in cluster 1 and 22.5% in cluster 3), although the difference was not statistically significant (P = .2789). Conclusions Age at diagnosis was a strong predictor of OA remission. The outcome of diisocyanate OA tended to be more favorable for patients with toluene diisocyanate OA allocated in cluster 2, but this finding needs to be validated by further data.

Background: A neurogenic pathway, involving TRPV1 expressed in the airways, has been hypothesized to be implicated in acute cardiovascular events occurring after peaks of air pollution. Aims: To test whether inhaled prostaglandin E2 (PGE2) and bradykinin (BK) modulate TRPV1 activity in vivo by changing cough response to capsaicin (CPS) and whether sensitization of TRPV1 by PGE2 and BK affects heart rate variability (HRV). Methods: 17 healthy volunteers (median age 35 IQR, 29.5-47) inhaled 100 μg PGE2, 200 μg BK or diluent in a randomized double-blind fashion. Subsequently, the response to CPS was assessed by cough challenge. The results were expressed as n° of coughs caused by 30 μM of CPS. HRV, expressed by low (0.04–0.15 Hz) and high (0.15–0.40 Hz) normalized frequency components (nLF, sympathetic component, and nHF, vagal component), as well as nLF/nHF ratio (sympathovagal balance), was evaluated after inhalation of diluent, PGE2 and BK. Results: Inhalations of PGE2 and BK were associated with a highly significant increase in cough response induced by CPS: PGE2 (n° cough=4.20±0.42; p Conclusion: Inhalation of PGE2 and BK sensitizes TRPV1 and is associated with autonomic dysregulation of cardiac rhythm in healthy subjects.

A neurogenic pathway, involving airway TRPV-1, has been implicated in acute cardiovascular events occurring after peaks of air pollution. We tested whether inhaled prostaglandin-E2 (PGE2) and bradykinin (BK) regulate TRPV-1 activity in vivo by changing cough response to capsaicin (CPS) and affecting heart rate variability (HRV), while also taking into account the influence of TRPV-1 polymorphisms (SNPs). Moreover, we assessed the molecular mechanism of TRPV-1 modulation in vitro. Seventeen healthy volunteers inhaled 100 μg PGE2, 200 μg BK or diluent in a randomized double-blind fashion. Subsequently, the response to CPS was assessed by cough challenge and the sympathetic activity by HRV, expressed by low (nLF) and high (nHF) normalized frequency components, as well as nLF/nHF ratio. Intracellular [Ca2+] was measured in HeLa cells, transfected with wild-type TRPV-1, pre-treated with increasing doses of PGE2, BK or diesel exhaust particulate (DEP), after CPS stimulation. Six functional TRPV-1 SNPs were characterized in DNA from each subject. Inhalation of PGE2 and BK was associated with significant increases in cough response induced by 30 μM of CPS (cough number after PGE2 = 4.20 ± 0.42; p p 2 = 6.1; p p 2 and BK, DEP directly activated TRPV-1. Inhalation of PGE2 and BK sensitizes TRPV-1 and is associated with autonomic dysregulation of cardiac rhythm in healthy subjects.

Background Cough is a common symptom in several respiratory diseases and may occur in healthy subjects as a defense mechanism against noxious inhalants. Cough response is mediated by transient receptor potential vanilloid-1 (TRPV1) expressed by C-fibers in the airways. Capsaicin (CPS) activates TRPV1 and is regularly used as a tool to study cough response. Although single nucleotide polymorphisms (SNPs) of TRPV1 are implicated in CPS binding, their role in cough response is not fully elucidated. Aims In this study we investigated the relationship between capsaicin cough challenge sensitivity and multiple TRPV1 polymorphisms. Methods The dose-response of cough induced by CPS inhalation was determined in 20 unselected healthy volunteers and the concentration of CPS causing two coughs (C2) was calculated. The SNPs I585V(rs8065080), T505A(rs17633288), T469I(rs224534), I315 M(rs222747), P91S(rs222749), and K2N(rs9894618) were characterized in blood DNA from each subject. The association between combinations of TRPV1 SNPs and CPS sensitivity of each subject was assessed by linear regression . Results All subjects were wild type for T505A and K2N, while they exhibited two to six SNPs with high capsaicin responsiveness. The major contribution to CPS sensitivity in vivo (C2) was due to four combined SNPs: 315 M, 585I, 469I and 91S (p = 0.015). We found, however, that the presence of a minimum of two polymorphisms, such as 91S combined with 315 M (p = 0.032) or 91S with 585I (p = 0.025), was sufficient to detect an effect on C2. Conclusion Capsaicin cough challenge sensitivity in healthy subjects is dependent on multiple TRPV1 polymorphisms.